Looking for Clues About How Proteins Talk to Each Other

UPTON, NY — Proteins perform distinct and very well-defined tasks, but
little is known about how interactions among them are structured at the
cellular level. Now, two physicists reveal that — at least in yeast cells
— these interactions are not random, but well organized. This result is
published in the May 3, 2002 issue of Science.

“Although scientists understand how a given protein interacts with
other proteins, the way they connect with each other as a whole remains
mysterious,” says Sergei Maslov, a physicist at the U.S. Department of
Energy’s Brookhaven National Laboratory, one of the study’s two authors.

For the last 10 years, Maslov, an expert in statistical physics, has
been studying complex systems such as collections of particles, proteins,
and networked computers. In the new study, Maslov and physicist Kim
Sneppen of the Norwegian University of Science and Technology used
computer modeling to look at how proteins interact with each other.

Although scientists know that some proteins are very busy “talking” to
many other proteins, Maslov and Sneppen discovered that such highly
connected proteins are unlikely to “talk” to each other. To illustrate
this intriguing phenomenon, Maslov uses the analogy of airline “hubs.”

“Each airline company has a network of flights connecting different
cities,” he says. “But when a city serves as a hub for one company, the
neighboring cities are mostly served by this company. Also, the hub is
served mainly by this company and not by another big company. So the two
big companies rarely ‘talk’ to each other.”

The network of 318 interactions among the 329
proteins that are present in the nucleus of yeast cells. Proteins
are represented by dots and their interactions by lines. Maslov and
Sneppen discovered that most of the neighbors of highly connected
proteins have few neighbors themselves.

The scientists think that proteins interact this way to reduce
interference among the messages of proteins that crisscross each other in
the cell. The other possible advantage of this protein interaction pattern
is to make the protein network inside the cell more stable. “Proteins with
many connections seem not to want to be disturbed by wrong messages or
anything ‘harmful’ to these proteins,” Maslov says.

To determine which among the 6,000 yeast proteins interact with each
other, Maslov and Sneppen collected data on protein interactions in yeast
cells from a public database. They then compared the resulting network of
interactions to a simulated pattern — produced by a computer-modeling
program — in which proteins interact randomly.

“If you took a given number of proteins and distributed interactions
among them randomly, you would hardly find any particular protein that
would have a lot of interactions. Proteins would all ‘talk’ randomly with
each other in such a network,” Maslov says. “So, hubs of
highly-interacting proteins are not something that you would expect to
happen by pure chance.”

But the scientists did observe hubs of interacting proteins in the
yeast cells. The connections between hub proteins reveal an “emergent
property” that acts beyond the level of the functions of the individual
proteins and makes them act together to coordinate their functions.
Studying these interactions can help identify these coordinated functions,
and may also reveal intrinsic features of the interacting proteins.

The “holistic” approach taken by Maslov is part of an ongoing
interdisciplinary effort in which scientists are trying to understand
phenomena involving many proteins, such as diseases. The understanding of
how protein interaction networks are designed might, for instance, help
scientists better understand the causes of cancer. One of the hubs in the
human protein network, called p53, has a major role in preventing cells
from developing into a tumor.

“The computer modeling program developed in this work can be applied to
interactions in other networks such as food webs in ecosystems, neural
networks, the Internet, and even among stock market agents,” Maslov says.

This work was funded by the U.S. Department of Energy’s Office of
Science, which supports basic research in a variety of scientific fields.

The
U.S. Department of Energy's Brookhaven National Laboratory conducts
research in the physical, biomedical, and environmental sciences, as
well as in energy technologies. Brookhaven also builds and operates
major facilities available to university, industrial, and government
scientists. The Laboratory is managed by Brookhaven Science
Associates, a limited liability company founded by Stony Brook
University and Battelle, a nonprofit applied science and technology
organization.